Aliphatic diols as analgesic agents

ABSTRACT

THE PRESENT INVENTION IS CONCERNED WITH THE USE OF A NUMBER OF ALIPHATIC DIOLS WHICH HAVE BEEN TESTED AND FOUND TO BE CENTRAL NERVOUS SYSTEM DEPRESSANTS. THESE COMPOUNDS ARE READILY SYNTHESIZED AND ARE USEFUL PHARMACOLOGICAL AGENTS. THESE COMPOUNDS ARE POLYALCOHOLS SUCH AS VARIOUS ALIPHATIC DIOLS WHICH ARE EXCELLENT ANALGESIC AND/OR ANESTHETIC AGENTS FOR ANIMALS AND HUMANS.

United States Patent 3 644 651 ALIPHATIC DIOLS As ANALGESIC AGENTS John W. Frankenfeld, Atlantic Highlands, and Horace W. Gerarde, Tenafly, N.J., assignors to Esso Research and The LD 'va1ue is obtained by empirically finding the dose at which 50% of the subject animals are killed. This is a standard method for measuring toxicity.

In accordance with the present invention, it has been Engineering Company found that the straight chain aliphatic diols are eflective No Drawing Filed Sept. 26, 1968 sen 762,972 central nervous system depressants having a low order CL 1 27 00 of toxicity. The materials of the present invention may US. Cl. 424-343 5 Claims be administered either orally or intravenously and may be nonaddictive. Thus, the present materials have a great potential for use in surgery and other medical applica ABSTRACT OF THE DISCL tions. Included in such applications are use as anesthetics The present invention is concerned with the use of for Surgery or as alialgesics q t relief. of sipce a number of aliphatic diols which have been tested and they possess ataractlc (tranflulhzmg) actlon thiise (hols found to be central nervous system depressants. These $3 1 li ff 5: 2 ggg g figis gg fig 15;: compounds are readily synthesized and are useful pharm n m y macological agents These compounds are polyalc oh 018 potefiial advantages over compounds in current use such such as various aliphatic diols which are excellent analf z i 3222 invention relates to several classes gesic and/or anesthetic agents for anlmals and humans. of aliphatic dihydroxy compounds (diols) of the follow ing general formulas:

FIELD OF INVENTION (1) RCHOHZCHZ ()H OH The present invention is concerned with the use of a new class of materials as anesthetic and analgesic agents g g g i g igfi g fi g z igg f igg g (n'alkyl) which are selected from the class of aliphatic diols and y g P are excellent for use with animals and humans. Particu- (2) ROHCHZOHOH larly desirable compounds are aliphatic diols containing OH OH l? l l i :g i z th where R represents a straight chain saturated (n-alkyl) is We nown 1n e ar 0 use various anes e 1c hydrocarbon group of carbon atoms. agents such as ether. However, ether has a number of ROH CH CH disadvantages which limit its use as, for example, its (3) 2 high flammability and explosivity. Also, it is relatively 0H 0H 381mg and 2): be gitglinlis tered intravengls y- In where R has the same connotation as above. or er to overcome t ese cu ties, Various 0 er ma- CH OH OH H terials such as chloroform, choral hydrate, paraldehyde (4) R m C 3 and certain tertiary alcohols have been suggested for 0H 0H this use. However, none of these have been able to rewhere R has the same connotation as above. place ether as the most common anesthetic. In recent (5) RCHNHCHZ years, barbiturates have been Widely used. These also 40 OH H have serious drawbacks and at times are dangerous to use 0 since they tend to become addictive. For purposes of com- Where R has the Same colmotatlon as aboveparison, some of the common anesthetic/ analgesic agents (6) cmwm crr, and their toxicity properties are shown in Table I. OH OH where x is an integral number ranging from 2-10. Ta lo I on al LD 1 These materials were found to be anesthetic agents. Comp n OT Choral hydrate ()5 k They are ettectlve central nervous system depressants yet Phenobarbital Sodium 5 k are not toxic. Especially useful are diols of the hexane Paraldehyde 3.5 /k (dogs). 50 serles. but other? y e p 9 Well- Barbital 0 6 (mice) Some of the aliphatic diols claimed 1n the present invention along with their toxicity data and some physical prop- :h D- ,M'k g fi $f Merck Index of clwmlcus and lugs em erties are listed in Table 2. These are only illustrative of TABLE 2 Approximate 1 B.P./mm. oral LDso Drols tested Class C.) Characteristics (rats) 1,3-pentanediol 1 78-81/0.5 Colorlessviscous 5ml./kg.

lggtigidzsvsgeet odor 1 G1 3.8 e. 1,3-hexanediol 1 8l82/0.2 Colorless, viscous 5ml./kg.

liquid, slight musty odor, sligtht bitter B. 1,3-deoanediol 1 Colorless solid 10 gJkg. 1,5hexanediol 3 112-114/10 Colorless. viscous GmL/kg.

liguid, musty 0 01. 2,5hexanedioL 4 126-128/8 Ctliilorlegs, viscous 2ml./kg.

l 1,2-butanediol- 5 7043/5 col i lessliquidnu- 16 gJkg. lA-butanediol 6 /5 Colorless liquid- 2ml./kg. 1.6-hexanediol 6 Colorless solid 5g./kg.

1 One ml. oi the liquid diols=approximately 0.8 g.

the classes of diols whose general formula-s were'given above. The present invention is by no means limited to the specific compounds giveriin Table 2. A comparison of Tables 1 and 2 clearly indicates that the present'compounds are less toxic than. other common anesthetics. In addition, rat feeding studies in which these materials were tested as sources of .dietary energy (calories), indicated that the compounds possess no irritating properties when used at moderate dosage.

Nevertheless these compounds are effective central nervous system depressants. The depressant action is manifested by decreased motor activity, tolerating side position, diminished rate and depth of respiration, and, in high dosage, profound coma. Of special importance is the observation that the animals were not affected by pain during the effective period. The depressant effect increased with the dose. In addition, the diols claimed in the present invention have desirable physical properties. They are either viscous liquids or low melting solids. They possess sufiicient water solubility to permit intravenous application in water or saline solution. These compounds may also be administered conveniently in the form of tablets, syrups, dragees, capsules, suppositories or in other forms apparent to those skilled in the art. In formulating tablets, pills and the like, the active compounds may be combined with suitable pharmaceutical carriers or binders such as corn starch or gelatin, flavoring agents such as cherry or orange flavor, peppermint oil and oil of Wintergreen and sweeteners such as sucrose, lactose or saccharin. A syrup may contain the active compound in combination with a flavoring agent, sweetener and a pharmaceutical carrier such as propylene glycol or glycerol. The diols may be incorporated in the formulations in amounts ranging from to- 50% by weight of the formulations depending upon the type of composition and desired dosage. A preferred composition for oral or intravenous application would contain from 50 mg. to 1 g. per unit dosage.

The diols may be prepared in any satisfactory manner. The most satisfactory procedures will depend upon the type of diol desired. For the 1,3-diols (class 1) the following methods are especially useful.

The Reformatsky reaction followed by reduction:

or by means of the Prins reaction of formaldehyde and the appropriate a olefin or mixtures of a olefins:

G3 H O RCHCHaCHz RCHZCHQ 110110 I OH OH Diols of class 2 are conveniently prepared by the acylation of ketones with esters followed by reduction of the resulting fi-diketone.

The class 3 diols are obtained by hydroboration and subsequent oxidation of the corresponding unsaturated ketone or alcohol with diborane.

ROHCHzCH2OH=CH 32H. R(|3H(OH CHz Y 8, 0H OH OH The 2,5-diols (class 4) may be prepared in a twostep procedure from substituted furans.

err-011' 0 .0 H25 4 II Ila/catalyst CH 'C\ OR OH C(CH;)2CR

our cmonmonn OH OH Class 5 diols are readily obtained by oxidation of the appropriate terminal olefins:

The a, w-CliOlS (class 6) are prepared by reduction of the readily available esters of dibasic acids:

R020 (CHzhC 02R EXAMPLE 1 Male albino rats werefasted overnight and then dosed by gastric intubation under light anesthesia using a Nelaton Fr. 8 rubber catheter attached to a glass syringe with 4 ml. per kilogram body weight of a 50% aqueous solution of 2,5-hexanediol. A short time after dosing, the animals exhibited central nervous system depressant effects. This was manifested by decreased motor activity, tolerating side position and diminished rate and depth of respiration. They were not affected by pain. The animals were observed for several days after dosing. After recovering from the depressant effects, they were normal in appearance and were gaining weight.

EXAMPLE 2 Male albino rats weighing from 260 to 300 grams were first fasted and then dosed with various aliphatic diols as described in Example 1 above. Two animals were closed at each of the following dose levels per kilogram body weight (an equal volume of water was added to each dose): 2 ml., 4 ml., 6 ml., 8 ml., and 10 ml. All animals exhibited the nervous system depressant effects described above to a more or less degree. The effects increased in intensity with the dose. At the higher levels the animals experienced profound coma and even death, presumably from respiratory failure. The results and observations made with various hexanediols are given in Table 3. The surviving animals were normal in appearance and behavior 'a few days after dosing and were gaining weight. The results in Table 3 demonstrate both the relatively low toxicity of these compounds and their action on the central nervous system.

TABLE 3 Mortality ratio at dose level (mL/kg. body wt.)

Diol Class 2 4 6 8 10 Observations 1,3-hexane 1 0/2 0/2 1/2 1/2 2/2 Moderate depressant at lowest levels; survivors normal in appearance. 1,5-hexane 3 0/2 0/2 0/2 1/2 l/2 Moderate depressant at lowest levels; survivors normal in appearance. 2,5-hexane 4 0/2 2/2 2/2 2/2 2/2 Strong depressant at all levels; survivors normal in appearance. 1,6-hexane 6 0/2 0/2 1/2 l/Z 2/2 Moderate depressant at low levels: survivors normal in appearance.

What is claimed is: 5. A process according to claim 1 in which said all- 1. A process for inducing analgesia in a human or phatic diol is 1,6-hexanediol. animal subject which comprises administering to said 15 human or animal subject in need of such treatment from References Cited about 50 mg. to 1 g. per dosage of an aliphatic dihydroxy UNITED STATES PATENTS compound (diol); said diol being a straight chain, aliphatic diol containing 6 carbon atoms with the hydroxyl ggiggg et groups situated on the first and second; first and third: 20

first and fifth; second and fourth; second and fifth; or the OTHER REFERENCES two terminal (IX-w) carbon atoms. Bottle et al., J. Pharmacy & Pharmacol, July 1958, pp.

2. A process according to claim 1 in which said aliphat- 447-449.

ic diol is 1,3-hexanediol. Wenzel et al., I. of American Pharm. Association, Sep- 3. A process according to claim 1 in which said aliphat- 25 (ember 19 9, PP- 669-672- ic diol is 1,5-hexanediol.

4. A process according to claim 1 in which said aliphat- JEROME GOLDBERG Pnmary Exammer ic diol is 2,5-hexanediol. V. D. TURNER, Assistant Examiner 

